Blocking B Cells may be the Key to Controlling NMOSD Over Time

Jeffrey Bennett, MD, PhD

Making transformative progress in the treatment of rare diseases can be challenging. But as we improve our understanding of the etiology of these diseases, we’re uncovering critical biological drivers that can be targeted through therapeutic intervention to deliver improvements in patient care.

One powerful example of this is in neuromyelitis optica spectrum disorder (NMOSD), a rare autoimmune disease caused by autoimmunity attacks against astrocytes in the central nervous system (CNS).¹ This inflammation leads to severe attacks of nervous system dysfunction that can result in serious, wide-ranging physical impairments and permanent disability.²

Inflammatory attacks in NMOSD are triggered by anti-aquaporin-4 antibodies (anti-AQP4-IgG), proteins that bind primarily to astrocytes in the CNS, causing an immune response that destroys the astrocytes. These antibodies, which are present in roughly 90% of people with NMOSD, are produced in part by mature B cells in the body (known as plasmablasts).^3,4

Research into the mechanisms that underlie NMOSD pathophysiology has identified that B cells play a key role in driving disease activity. In particular, studies have indicated that certain B-cell populations are increased in NMOSD patients.^1,5 These B-cell populations bear a common cell surface lineage marker, CD19. Therefore, depletion of CD19 B cells might offer a therapeutic avenue for reducing NMOSD attacks and improving patient outcomes.^1,6

The N-MOmentum clinical trial (NCT02200770) was conducted to evaluate the anti-CD19 B-cell-depleting humanized monoclonal antibody UPLIZNA® (inebilizumab-cdon), which was approved by the U.S. Food and Drug Administration for adults with NMOSD who are anti-AQP4-IgG positive.⁷ The monoclonal antibody binds directly to CD19 on the surface of B cells, targeting B cells from early development through to the stage of antibody secretion. Antibody secreting plasmablasts and plasma cells are not directly targeted by current anti-CD20 B-cell-depleting therapeutics.⁶

The N-MOmentum trial provided important insights about the impact of B cell depletion on the clinical effects of NMOSD. Importantly, depleting B cells in study participants was associated with improved outcomes.^7,8 At six months, participants with lower B-cell counts had improved clinical and imaging metrics of disease activity. 89% of AQP4-antibody positive participants were attack free after 28 weeks of treatment with UPLIZNA.⁷ In addition, lower B-cell levels measured at the end of the trial’s randomized control period were predictive of stable, deep depletion during the long-term, open-label period, resulting in a 97% reduction in annualized attack rate (AAR) after 2.5 years of treatment.⁸

Ultimately, the findings from this study provide useful insights about the clinical and radiologic benefits of managing NMOSD with anti-CD19 B-cell depletion as well as help to sharpen our understanding of the fundamental biology of this rare disease.⁸ The result has enhanced optimism for the long-term outlook for NMOSD patients as regular monitoring of B-cell counts may be a useful approach to guide patient care over time as a strategy to reduce NMOSD attacks and their associated damage.

References:

1. Bennett JL, O’Connor KC, Bar-Or A, et al. B lymphocytes in neuromyelitis optica. Neurol Neuroimmunol Neuroinflamm. 2015;2(3):e104. doi:10.1212/NXI.0000000000000104
2. Ajmera MR, Boscoe A, Mauskopf J, Candrilli SD, Levy M. Evaluation of comorbidities and health care resource use among patients with highly active neuromyelitis optica. J Neurol Sci. 2018;384:96-103
3. Prain K, Woodhall M, Vincent A et al. AQP4 Antibody Assay Sensitivity Comparison in the Era of the 2015 Diagnostic Criteria for NMOSD. Front. Neurology. 2019; https://doi.org/10.3389/fneur.2019.01028
4. Hyun JW, Jeong IH, Joung A, Kim SH, Kim HJ. Evaluation of the 2015 diagnostic criteria for neuromyelitis optica spectrum disorder. Neurology. 2016;86(19):1772-1779. doi:10.1212/WNL.0000000000002655.
5. Kowarik, MC et al. CNS Aquaporin-4-specific B cells connect with multiple B-cell compartments in neuromyelitis optica spectrum disorder. Ann Clin Transl Neurol. 2017;4:369-380
6. Forsthuber TG, Cimbora DM, Ratchford JN, Katz E, Stüve O. B cell-based therapies in CNS autoimmunity: differentiating CD19 and CD20 as therapeutic targets. Ther Adv Neurol Disord. 2018;11:1-13. doi:10.1177/1756286418761697
7. UPLIZNA (inebilizumab-cdon) [prescribing information] Horizon.
8. Bennett JL, Atkas O, Smith M, Rees WA, Katz E and Cree B. Extent of B-cell depletion is associated with disease activity reduction in neuromyelitis optica spectrum disorder: results from the N-MOmentum study. Poster presented at 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis. (ECTRIMS 2021); October 2021; Virtual.